| Note | |
| Note | Determination of the NAT2 genotype or phenotype has been proposed to predict adverse reactions in patients with tuberculosis receiving isoniazid, prior to the concomitant administration of drug combinations such as procainamide-phenytoin or doxiciline-rifampin. In addition, several human diseases have been related to NAT2 polymorphism. There are described below. |
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| Entity | Brain cancer |
| Prognosis | Preliminary findings argue for association of a trend towards higher risk in individuals classified as NAT2 homozygous rapid acetylators in patients with astrocytoma or meningioma. |
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| Entity | Lung cancer |
| Prognosis | Several studies based on an initial hypothesis that slow acetylation may increase the risk of developing lung cancer have been conducted. This hypothesis has been reinforced by studies indicating that slow acetylation, especially if it is associated to defect genotypes for other phase II enzymes, may confer increased susceptibility to the formation of adducts. Several studies have concluded that the NAT2 slow acetylation genotype causes a marginally increased risk of developing lung cancer. In spite of these findings, present evidence suggests that the NAT2 polymorphism alone does not constitute a relevant risk factor for lung cancer. However this polymorphism may reinforce the effect of other genetic and/or environmental factors. |
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| Entity | Liver cancer |
| Prognosis | A role for xenobiotic-metabolising enzymes in liver carcinogenesis is to be expected among patients with environmentally-related liver cancer since, besides viral hepatitis, liver cancer may be related to environmental substances. The findings obtained in patients with primary liver cancer not related to viral hepatitis are consistent and indicate a minor, but relevant, association of the slow NAT2 acetylation status and predisposition to liver cancer. |
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| Entity | Colorectal cancer |
| Prognosis | The hypothesis that acetylator status may predispose to a determined cancer risk is based on a differential effect of N-acetylation as a potential detoxification step and O-acetylation as a potential carcinogen-activation step. In the case of colorectal cancer it was hypothesized that O-acetylation is more relevant that N-acetylation, and therefore the rapid acetylation genotype is the putative risk status associated with colorectal cancer. Sufficient evidence is available to rule out a relevant association of NAT genotypes alone with colorectal cancer risk. However, the putative interaction of meat consumption and the NAT2 genotype deserves particular attention. |
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| Entity | Bladder cancer |
| Prognosis | Despite the large number of studies and meta-analyses performed in several human populations, current evidence is not sufficient to confirm unambiguously an association of NAT2 polymorphism to overall bladder cancer risk. A general association of the slow acetylation status with bladder cancer risk has not been fully confirmed, although meta-analyses have obtained positive findings for a modest association of the slow NAT2 acetylation genotype with bladder cancer risk, with odds ratio values between 1.3 and 1.5. Furthermore, the biological basis for the putative association is uncertain. In diverse independent studies, mutagenicity in urine was tested in individuals exposed to urban pollution, smoking, red meat intake or textile dyes. In all cases, no higher mutagenicity in slow NAT2 acetylators could be established when compared to these or rapid acetylators, and in fact among individuals exposed to urban pollution, rapid acetylators showed a higher mutagenicity in urine than slow acetylators. In a study investigating the influence of NAT genotypes in the association between permanent hair dyes and bladder cancer, a significant association of the slow NAT2 acetylation genotype was identified. However these findings could not be replicated in other studies. |
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| Entity | Breast cancer |
| Prognosis | After dozens of studies involving several thousands of breast cancer patients, as well as meta-analyses, today it is obvious that no major association of NAT2 polymorphism and breast cancer risk exists. |
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| Entity | Head and neck cancer |
| Prognosis | Since chemical compounds present in tobacco are inactivated by phase II enzymes, it has been proposed that head and neck cancer risk could be modified by NAT genotypes. However, overall findings indicate that no relevant association between NAT2 polymorphism and head and neck cancer risk is to be expected. |
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| Entity | Other diseases |
| Disease | Although a relation of risk may be definitely discarded for systemic lupus erythematosus (SLE), inflammatory bowel disease and endometriosis, more research is needed for rheumatoid arthritis, Parkinson's, Alzheimer's, Behçet's and periodontal diseases, as current results are inconclusive but suggest a possible relation with NAT2 polymorphism. In diabetes mellitus the possible relation with the rapid phenotype may be due to acquired metabolic changes and more genotyping studies are needed. NAT2 slow metabolizers are more prone to the side effects of polymorphically acetylated drugs, as is the SLE-like syndrome induced by hydralazine and procainamide, the side effects due to sulphasalazine and the skin rash secondary to many sulphonamides. |
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| Unraveling ambiguous NAT2 genotyping data. |
| Agundez JA, Golka K, Martinez C, Selinski S, Blaszkewicz M, Garcia-Martin E. |
| Clin Chem. 2008 Aug;54(8):1390-4. |
| PMID 18664443 |
| |
| N-acetyltransferases: lessons learned from eighty years of research. |
| Agundez JA. |
| Curr Drug Metab. 2008 Jul;9(6):463-4. |
| PMID 18680465 |
| |
| N-acetyltransferases as markers for asthma and allergic/atopic disorders. |
| Batra J, Ghosh B. |
| Curr Drug Metab. 2008 Jul;9(6):546-53. |
| PMID 18680475 |
| |
| Molecular mechanism of slow acetylation of drugs and carcinogens in humans. |
| Blum M, Demierre A, Grant DM, Heim M, Meyer UA. |
| Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5237-41. |
| PMID 1675794 |
| |
| Human arylamine N-acetyltransferase genes: isolation, chromosomal localization, and functional expression. |
| Blum M, Grant DM, McBride W, Heim M, Meyer UA. |
| DNA Cell Biol. 1990 Apr;9(3):193-203. |
| PMID 2340091 |
| |
| Regulation of arylamine N-acetyltransferases. |
| Butcher NJ, Tiang J, Minchin RF. |
| Curr Drug Metab. 2008 Jul;9(6):498-504. |
| PMID 18680469 |
| |
| Genetically determined variability in acetylation and oxidation. Therapeutic implications. |
| Clark DW. |
| Drugs. 1985 Apr;29(4):342-75. |
| PMID 2859977 |
| |
| Possible implications of doxycycline-rifampin interaction for treatment of brucellosis. |
| Colmenero JD, Fernandez-Gallardo LC, Agundez JA, Sedeno J, Benitez J, Valverde E. |
| Antimicrob Agents Chemother. 1994 Dec;38(12):2798-802. |
| PMID 7695265 |
| |
| Agranulocytosis during combined procainamide and phenytoin therapy. |
| Crook JE, Woosley RL, Leftwich RB, Natelson EA. |
| South Med J. 1979 Dec;72(12):1599-601. |
| PMID 515773 |
| |
| Genetic control of isoniazid metabolism in man. |
| Evans DA, Manley KA, McKusick VA. |
| Br Med J. 1960 Aug 13;2(5197):485-91. |
| PMID 13820968 |
| |
| The determination of the isoniazid inactivator phenotype. |
| Evans DA, Storey PB, Wittstadt FB, Manley KA. |
| Am Rev Respir Dis. 1960 Dec;82:853-61. |
| PMID 13697556 |
| |
| Interethnic and intraethnic variability of NAT2 single nucleotide polymorphisms. |
| Garcia-Martin E. |
| Curr Drug Metab. 2008 Jul;9(6):487-97. |
| PMID 18680468 |
| |
| Nucleotide sequence of an intronless gene for a human arylamine N-acetyltransferase related to polymorphic drug acetylation. |
| Grant DM, Blum M, Demierre A, Meyer UA. |
| Nucleic Acids Res. 1989 May 25;17(10):3978. |
| PMID 2734109 |
| |
| Evidence for two closely related isozymes of arylamine N-acetyltransferase in human liver. |
| Grant DM, Lottspeich F, Meyer UA. |
| FEBS Lett. 1989 Feb 13;244(1):203-7. |
| PMID 2924904 |
| |
| Structures of human arylamine N-acetyltransferases. |
| Grant DM. |
| Curr Drug Metab. 2008 Jul;9(6):465-70. |
| PMID 18680466 |
| |
| Molecular genetics of human polymorphic N-acetyltransferase: enzymatic analysis of 15 recombinant wild-type, mutant, and chimeric NAT2 allozymes. |
| Hein DW, Ferguson RJ, Doll MA, Rustan TD, Gray K. |
| Hum Mol Genet. 1994 May;3(5):729-34. |
| PMID 8081359 |
| |
| Influence of polymorphic N-acetyltransferases on non-malignant spontaneous disorders and on response to drugs. |
| Ladero JM. |
| Curr Drug Metab. 2008 Jul;9(6):532-7. |
| PMID 18680473 |
| |
| Human N-acetyltransferases and drug-induced hepatotoxicity. |
| Makarova SI. |
| Curr Drug Metab. 2008 Jul;9(6):538-45. |
| PMID 18680474 |
| |
| Effect of environmental substances on the activity of arylamine N-acetyltransferases. |
| Rodrigues-Lima F, Dairou J, Dupret JM. |
| Curr Drug Metab. 2008 Jul;9(6):505-9. |
| PMID 18680470 |
| |
| Arylamine N-acetyltransferases in mycobacteria. |
| Sim E, Sandy J, Evangelopoulos D, Fullam E, Bhakta S, Westwood I, Krylova A, Lack N, Noble M. |
| Curr Drug Metab. 2008 Jul;9(6):510-9. |
| PMID 18680471 |
| |
| Structure of arylamine N-acetyltransferase reveals a catalytic triad. |
| Sinclair JC, Sandy J, Delgoda R, Sim E, Noble ME. |
| Nat Struct Biol. 2000 Jul;7(7):560-4. |
| PMID 10876241 |
| |
| Structure/function evaluations of single nucleotide polymorphisms in human N-acetyltransferase 2. |
| Walraven JM, Zang Y, Trent JO, Hein DW. |
| Curr Drug Metab. 2008 Jul;9(6):471-86. |
| PMID 18680467 |
| |
| The mechanism of isoniazid acetylation by human N-acetyltransferase. |
| Weber WW, Cohen SN. |
| Biochim Biophys Acta. 1968 Jan 8;151(1):276-8. |
| PMID 5678219 |
| |
| Structural basis of substrate-binding specificity of human arylamine N-acetyltransferases. |
| Wu H, Dombrovsky L, Tempel W, Martin F, Loppnau P, Goodfellow GH, Grant DM, Plotnikov AN. |
| J Biol Chem. 2007 Oct 12;282(41):30189-97. Epub 2007 Jul 26. |
| PMID 17656365 |
| |
